OCT 10, 2018 9:00 AM PDT

Using Radiotherapy, Tumor-Reactive mAb and IL2 to Engage Innate and Adaptive Antitumor Immunity

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Professor of Pediatrics, Department of Human Oncology & Genetics, University of Wisconsin-Madison
    Biography
      Paul Sondel, M.D., Ph.D. is the Reed and Carolee Walker Professor of Pediatrics, Human Oncology and Genetics and Director of Research for the Division of Pediatric Hematology, Oncology and BMT at the University of Wisconsin - Madison (UW). He has focused on basic, translational and clinical cancer immunotherapy since 1969. Following BS-1971 and Ph.D.- 1975 (UW, mentored by BMT pioneer, Fritz Bach, M.D), M.D.- 1977 (Harvard Medical School) and residencies at U. of Minnesota and UW, he joined the UW faculty in 1980. He was Head of PHO-BMT from 1990 - 2016, and helped lead cancer immunology research at the UW-Carbone-Cancer-Center (UWCCC) since 1990. His laboratory has pursued strategies for enabling immune responses to impact on cancer; some have moved into clinical testing in adults at the UWCCC and in children through the COG. This includes collaborative development of an FDA-approved immunotherapy regimen (dinutuximab+ IL2+ GM-CSF) for children with neuroblastoma. He has held multiple committee/leadership roles, including at The NIH/NCI, American Cancer Society, Children's Oncology Group, and St. Jude's Children's-Research-Hospital. He has been a scholar of the Leukemia Society of America, recently received a 7-year Outstanding Investigator Award from the NCI, and the SITC's Smalley Award for 2017. He has published more than 390 scientific articles and chapters, and trained more than 70 graduate students and post-doctoral fellows in his lab. He also enjoys biking and canoeing; but most of all, he and his wife of 45 years (Sherie) love being parents and grandparents.

    Abstract

    In prior work, we have pursued how tumor reactive monoclonal antibody (mAb), together with activators of innate immune cells, like NK cells, can augment antibody dependent cell-mediated cytotoxicity (ADCC) of cancer cells in vitro. Following preclinical development in mice, this work has been translated into clinical efficacy in the setting of maintenance therapy for high risk neuroblastoma, and the FDA approval of the anti-GD2 mAb, dinutuximab. We have shown how the genotype of patients for NK inhibitory KIR genes can influence the activity of this therapy. More recently, we have identified a novel combination therapy (“In Situ Vaccination”) given directly to a large existing tumor that enables it to function as a potent vaccine, providing long-lasting cure of mice from large tumors that were previously non-curable with other immunotherapy approaches. Following local radiotherapy (RT), we directly inject a tumor-reactive immunocytokine [a tumor-reactive anti-GD2 mAb linked to IL2, a potent immune cell activator]. Most mice bearing a single large melanoma show tumor elimination with long lasting protective immunity with this approach (Morris et al, Cancer Research, 76:3929, 2016). In mice with 2 tumors, delivering RT to both the 1st + 2nd tumors, or adding checkpoint-blockade therapy using an anti-CTLA-4 mAb, enables injection of immunocytokine to the 1st tumor to eradicate it as well as the 2nd tumor in most mice. (Morris et al, Cancer Immunology Research,6: 825-834, 2018). Clinical testing in melanoma is being initiated. Preliminary results are similar in mice bearing pancreatic cancer or neuroblastoma, and clinical translation in neuroblastoma has been started. We hypothesize that In Situ Vaccination will also be effective in other tumors that appear resistant to checkpoint-blockade.

    Learning Objectives: 

    1. Immune responses can be induced against “cold” tumors
    2. Combined approaches, activating presentation and recognition,  blocking an immunosuppressive micro-environment, and “taking off the brakes” can be synergistic.


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